Interaction of huntingtin fragments with brain membranes -: clues to early dysfunction in Huntington's disease
Interaction of huntingtin fragments with brain membranes -: clues to early dysfunction in Huntington's disease
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DOI：
10.1111/j.1471-4159.2005.03620.x
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发表时间：
2006-02-01
影响因子：
4.7
通讯作者：
Wanker, EE
中科院分区：
文献类型：
--
作者：
Suopanki, J;Götz, C;Wanker, EE
亨廷顿蛋白是大脑中一种功能未知的大型多结构域蛋白质。N端异常拉长的聚谷氨酰胺导致亨廷顿病(HD)，这是一种进行性神经退行性疾病。亨廷顿蛋白被认为通过参与内吞和胞吐的蛋白质在膜转运中发挥作用。在这里，我们提供了亨廷顿蛋白和膜之间直接联系的证据。在患有HD的R6/2小鼠脑内，在4-8周龄的症状前期，突触后膜中有一个kDa的N末端亨廷顿蛋白片段积聚。此外，在8周龄时检测到一个约200 kDa的寡聚片段。两栖动物蛋白、突触素以及NMDA受体和AMPA受体亚单位分布的同步渐进性变化提供了突触运输功能障碍的强烈迹象。突触膜中主要磷脂的组成不受影响。在体外，脑脂的大单层小泡很容易与可溶的N-末端亨廷顿蛋白外显子1片段相关联，并刺激突变的亨廷顿蛋白聚集体的纤维形成。此外，突变型和野生型Huntingtin外显子1片段与脑脂类物质的相互作用引起了双层干扰，这种干扰是通过多聚谷氨酰胺附近的富含脯氨酸的区域进行的。这表明体内的脂质相互作用可能影响亨廷顿蛋白的错误折叠，并可能在HD的发病机制中发挥早期作用。
Huntingtin is a large, multi-domain protein of unknown function in the brain. An abnormally elongated polyglutamine stretch in its N-terminus causes Huntington's disease (HD), a progressive neurodegenerative disorder. Huntingtin has been proposed to play a functional role in membrane trafficking via proteins involved in endo- and exocytosis. Here, we supply evidence for a direct association between huntingtin and membranes. In the brains of R6/2 mice with HD pathology, a 64 kDa N-terminal huntingtin fragment accumulated in postsynaptic membranes during the pre-symptomatic period of 4-8 weeks of age. In addition, an oligomeric fragment of approximately 200 kDa was detected at 8 weeks of age. Simultaneous progressive changes in distribution of amphiphysin, synaptojanin, and subunits of NMDA- and AMPA-receptors provide a strong indication of dysfunctional synaptic trafficking. Composition of the major phospholipids in the synaptic membranes was unaffected. In vitro, large unilamellar vesicles of brain lipids readily associated with soluble N-terminal huntingtin exon 1 fragments and stimulated fibrillogenesis of mutant huntingtin aggregates. Moreover, interaction of both mutant and wild-type huntingtin exon 1 fragments with brain lipids caused bilayer perturbation, mediated through a proline-rich region adjacent to the polyglutamines. This suggests that lipid interactions in vivo could influence misfolding of huntingtin and may play an early role in HD pathogenesis.